Process for the preparation of deactivated anilines

ABSTRACT

The present invention is directed to a process for the preparation of deactivated anilines, which comprises the step of reacting a compound of formula ( I ) ##STR1## with a dialkylamide in the presence of a base at elevated temperature, in which: 
     R 1  is chosen from groups whose anions (R 1   - ) constitute leaving groups; 
     R 2  and R 4 , which may be the same or different, are chosen from hydrogen, hydrocarbon chains, halogens and groups which are electron-attracting (EAG); 
     R 3  is chosen from hydrocarbon chains, halogens and groups which are electron-attracting, preferably through an inductive effect rather than a mesomeric effect; 
     with the proviso that at least one of the groups R 2 , R 3 , and R 4  is electron-attracting through an inductive effect. 
     A second embodiment of the present invention is directed to a process for the dealkylation of deactivated anilines which comprises the steps of free radical halogenation of the benzyl carbon followed by hydrogenation. A third embodiment of the present invention is directed to a process for the dealkylation of deactivated anilines which comprises the step of reacting an alkylated aniline with an amine in the presence of a catalytic amount of a pyridine salt. 
     A fourth embodiment of the present invention is direct to intermediates for the preparation of deactivated anilines which have the formula (III) 
     
         Ar--N(--CH.sub.2-x Z.sub.x --R.sub.1 &#39;)(--CH.sub.2-y Z.sub.y --R.sub.2 
    
      &#39;)(III) 
     wherein 
     Z represents a halogen atom; 
     R 1  &#39; and R 2  &#39;, which may be the same or different, are each a hydrogen atom or an alkyl radical having at most 4 carbons; 
     x and y, which may be the same or different, are each an integer of 0 or 1, with the proviso that x+y is at least equal to 1; and 
     Ar is a deactivated aromatic ring, preferably derived from formula (I) by replacement of R 1  with a dialkylamine.

This is a division of application Ser. No. 08/156,633, filed Nov. 24,1993, now U.S. Pat. No. 5,401,882.

The present invention is directed to processes for the synthesis ofdeactivated anilines. The present invention is also directed to aprocess of grafting a monoalkylamine or dialkylamine onto a deactivatedaromatic ring. The present invention is further directed to a processfor the dealkylation of deactivated anilines and novel intermediatecompounds useful for the preparation of deactivated anilines.

The synthesis of anilines has generally been performed by hydrogenationof aromatic nitro compounds. This technique, however, is subject to alarge number of constraints which limit its practical usefulness. Forexample, hydrogenation is not appropriate when other substituents, oreven the reaction products, are sensitive to hydrogenolysis. Nor ishydrogenation appropriate when it gives rise to a large number of sidereactions.

Moreover, the positioning of the nitro function on the aromatic ring maybe difficult, necessitating a complex multistep synthesis and the use ofexpensive reagents. Accordingly, there is a need for a direct and facilemethod for the preparation of deactivated anilines.

With respect to the dealkylation of deactivated anilines, the usualmethod for demethylating anilines employs aqueous hydrobromic acid(HBr), the use of which runs the risk of destroying other functionalgroups which may be present on the ring. Such functional groups whoselability is well-known include halogenated groups, in particular groupswhich are perhalogenated at the benzyl position, such astrifluoromethyl. There is, therefore, a need for a simple and effectiveprocess for dealkylating deactivated anilines.

As used herein, the term "deactivated aniline" is intended to denote anyamine linked directly to an electron-depleted aromatic ring-system suchthat the associated acid possesses a pKa no greater than 2, preferablyno greater than 1. Thus, aniline should be understood to include notonly aniline itself, but also the chemical compounds originating fromthe substitution of aniline, including anilines associated with otherring-system(s), for example, naphthylamines. The electron depletion ofthe ring-system may be due to any cause known to those skilled in theart, such as the presence of electron-attracting group(s) ("EAG"), whichare also known as electron withdrawing groups, or the presence of ahetero atom in one of the rings of a multi-ring system.

SUMMARY OF THE INVENTION

In a first embodiment, the present invention is directed to a processfor the preparation of deactivated anilines, which comprises the step ofreacting a compound of formula (I) ##STR2## with a dialkylamide in thepresence of a base at elevated temperature, in which:

R₁ is chosen from groups whose anions (R₁ ⁻) constitute leaving groups;

R₂ and R₄, which may be the same or different, are chosen from hydrogen,hydrocarbon chains, halogens and groups which are electron-attracting(EAG);

R₃ is chosen from hydrocarbon chains, halogens and groups which areelectron-attracting, preferably through an inductive effect rather thana mesomeric effect;

with the proviso that at least one of the groups R₂, R₃, and R₄ iselectron-attracting through an inductive effect.

A second embodiment of the present invention is directed to a processfor the dealkylation of deactivated anilines which comprises the stepsof free radical halogenation of the benzyl carbon followed byhydrogenation.

A third embodiment of the present invention is directed to a process forthe dealkylation of deactivated anilines which comprises the step ofreacting an alkylated aniline with an amine in the presence of acatalytic amount of a pyridine salt.

A fourth embodiment of the present invention is direct to intermediatesfor the preparation of deactivated anilines which have the formula (III)

    Ar--N(--CH.sub.2-x Z.sub.x --R.sub.1 ')(--CH.sub.2-y Z.sub.y --R.sub.2 ')(III)

wherein

Z represents a halogen atom;

R₁ 'and R₂ ', which may be the same or different, are each a hydrogenatom or an alkyl radical having at most 4 carbons;

x and y, which may be the same or different, are each an integer of 0 or1, with the proviso that x+y is at least equal to 1; and

Ar is a deactivated aromatic ring, preferably derived from formula (I)by replacement of R₁ with a dialkylamine.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

A first embodiment of the present invention is directed to a process forthe preparation of deactivated anilines, which comprises the step ofreacting a compound of formula (I) ##STR3## with a dialkylamide in thepresence of a base at elevated temperature, in which:

R₁ is chosen from groups whose anions (R₁ ⁻) constitute leaving groups;

R₂ and R₄, which may be the same or different, are chosen from hydrogen,hydrocarbon chains, halogens and groups which are electron-attracting(EAG);

R₃ is chosen from hydrocarbon chains, halogens and groups which areelectron-attracting, preferably through an inductive effect rather thana mesomeric effect;

with the proviso that at least one of the groups R₂, R₃, and R₄ iselectron-attracting through an inductive effect.

Optionally, the aromatic ring may also be substituted at one or both ofthe positions meta to R₁. If substituted, the substituents arepreferably groups which exert at least as much electron attractionthrough an inductive effect as alkyl groups, such as halogen atoms andpseudohalogens. The substituent(s), however, must be of an appropriatesize so as not to sterically hinder the reaction.

R₁ may be any functional group whose anion is a leaving group,preferably a good leaving group; as used herein, the term "good leavinggroup" refers to those moieties for which the acid associated with theanion possesses a pKa value no greater than 1. Preferably, R₁ is a groupfor which the acid associated with the anion has a pKa no greater than0; more preferably, the pKa of the acid is no greater than -1.Preferably, R₁ is a halogen atom, such as bromine or chlorine. Mostpreferably, R₁ is chlorine.

Preferably, either as a result of the nature of the functional group oras a result of the arrangement of EAG's on the aromatic ring, the anionsR₁ ⁻ constitute better leaving groups than anions derived from theradicals R₂ to R₄.

R₂ and R₄, which may be the same or different, are each chosen fromhydrogen, hydrocarbon chains, halogens and EAG's. Preferably, the EAG'sattract electrons through an inductive effect, as opposed to amesomeric, or resonance, effect. Suitable EAG's include pseudohalogens,alkoxycarbonyl groups, halogen atoms such as fluorine, chlorine andbromine, and perhaloalkyl groups. Of the halogen atoms, chlorine is apreferred EAG.

As used herein, the term "pseudohalogen" is intended to mean radicalscapable of forming an anionic leaving group for which the acidassociated with the anion has a pKa of no greater than 1. Preferably,the acid associated with the anion has a pKa no greater than 0; morepreferably, no greater than -1.

Preferably, the EAG's are perhaloalkyl groups. More preferably, theEAG's are trihalomethyl groups; most preferably, the EAG's aretrifluoromethyl groups. As used herein, the term "perhaloalkyl" isintended to mean groups having the formula

    R--(CX.sub.2).sub.n --

wherein

n is equal to at least 1 and, where R is not an electron-attractinggroup, preferably equal to 2,

each X is, independently, a halogen atom, preferably fluorine orchlorine, and

R is a C₁ to C₁₀ hydrocarbon, alkyl or aryl residue, or a halogen atom.

If a hydrocarbon, R preferably has from 1 to 6 carbon atoms, morepreferably, from 1 to 4 carbon atoms. Most preferably, R is an EAG, suchas a halogen atom.

The groups X are most often identical. Generally, n is an integer of notmore than 10. Preferably, when the perfluoroalkyl group is at the orthoposition, n is an integer less than 6 and more preferably less than 4.The perhaloalkyl group must be of an appropriate size so as not tosterically hinder the reaction.

R₃ is chosen from hydrogen, hydrocarbon chains, halogens and EAG's whichare electron-attracting through an inductive effect but not a mesomericeffect.

Optionally, R₂ and/or R₄ may, together with the substituent at therespective adjacent position meta to R₁, form at least one additionalaromatic ring, such as a naphthalene, anthracene, phenanthrene orchrysene ring system. The additional aromatic ring(s) may, of course, besubstituted.

Among suitable bases which can be used in the inventive process, anionicbases are preferred, such as carbonates. Preferably, the base is chosenfrom among alkali metal oxides, alkali metals amides and alkali metalhydroxides and alcoholares. Preferably, the pKa of the conjugate acid ofthe base employed is at least equal to 9, more preferably 10, and mostpreferably 12. For economic reasons, sodium hydroxide is a particularlypreferred base.

The amide used in the inventive process is preferably a dialkylamide ofa carboxylic acid. More preferably, the amide is a dialkylamide of acarboxylic acid having not more than 10 carbon atoms. It is alsopossible to use dialkylamides such as tetramethylureas andtetramethylguanidines. Preferably, the dialkylamides aredialkylformamides. Preferably, the dialkylformamides are such that thenumber of carbon atoms in the alkyl radicals grafted to the nitrogen isnot more than 6. More preferably, the number of carbon atoms is not morethan 4 and most preferably not more than 3. Methyl derivatives are theparticularly preferred derivatives.

The reaction of a dialkylamide and a compound having formula Ipreferably takes place at a temperature of between 150° and 300° C., andmore preferably between 180° and 250° C.

The solvent employed in the present process can be any solvent ormixture of solvents which does not decompose under reaction conditionsand is inert with respect to the reactants. Preferably the solvent ispolar, i.e., has a dielectric constant ε equal to at least 30. When thesolvent is protic, the solvent should possess a pKa preferably at leastequal to 14, the pKa of water. When there is a single solvent, it ispreferable to use either an excess of reactants or an excess ofsubstrate.

It should be noted that the reaction system tolerates hydroxylatedderivatives, such as water, as solvents, particularly when a coppercompound is used as a catalyst for the reaction. Thus, in a preferredembodiment, the reaction is carried out in the presence of from 0.1 mol%to 1.0 mol% of a cuprous salt relative to the substrate. Examples ofsuitable cuprous salts are cuprous chloride and cuprous acetate.

Preferably, the amounts of reactants and catalysts introduced are asfollows, taking as reference the quantity of the compound of formula Iequal to 1:

base: from 0.5 to 5 gram-equivalents, preferably from 2 to 4gram-equivalents; and

amide: 1 to 100 gram-equivalents, preferably from 5 to 25gram-equivalents.

The reaction takes place in an autoclave at the normal pressure of thereactants under the experimental conditions. Although not essential, itis preferred that the reaction take place in an inert atmosphere, forexample, under nitrogen or under argon.

According to the present invention, it has been possible to preparepara-trifluoromethyl-N,N-dimethylanilines in a single step from thecorresponding halogenated derivatives. The results observed aregenerally better when the starting material is a dihalogenated ortrihalogenated derivative at the meta and para positions of aperfluoroalkyl electron-attracting function.

Preferably, there are no more than four substituents on the aromaticring. In such an embodiment of the present invention, R₁ is chlorine orbromine, preferably chlorine; R₂ is fluorine, chlorine or bromine,preferably chlorine; the position meta to R₁ is hydrogen, fluorine,chlorine or bromine, preferably chlorine; and R₃ is perfluoroalkyl, ingeneral trifluoromethyl.

However, the tertiary aniline compounds obtained by this embodiment ofthe present invention may not all be useful directly; the primary or thesecondary aniline may, in certain applications, be even more useful thanthe corresponding tertiary aniline.

Accordingly, a second embodiment of the present invention is directed toa process for the dealkylation of deactivated anilines, which comprisesfree radical halogenation of an alkylated deactivated aniline followedby hydrolysis of the halogenated product. Preferably, the deactivatedaniline has the formula II ##STR4## in which R₁ represents a mono- ordialkylamino radical and R₂ through R₄ are as defined above.Additionally, the positions meta to R₁ may optionally be substituted asbefore.

The free radical halogenation is carried out under conditions which aregenerally known to those skilled in the art, preferably conditionsinvolving initiation of the reaction by electromagnetic radiation ofsuitable wavelength, peroxides or other equivalent initiators.

The halogenating agent is preferably the molecular or atomic halogen.Alternatively, the halogenating agent may be any compound known to thoseskilled in the art which can generate a halogen free radical. Suchcompounds include thionyl or sulfuryl halides, such as thionyl chloride,phosphorous pentachloride, mixtures of PCl₃ /Cl₂, alkyl hypochloritesand compounds of the type X₂ O, in which X is a halogen other thanfluorine or iodine. In the case of bromine, mention should be made, whenthey are stable and not too toxic, of the compounds corresponding to theabove chlorine compounds, as well as compounds of the N-bromosuccinimide(NBS) type. In the case of iodine, the best iodinating agent remainsmolecular iodine.

In a first stage of the free radical halogenation, if either R₂ or R₄are hydrogen, these positions are halogenated by the free radicalhalogenating agent. In a second stage, one or both of the alkyl groupsis monohalogenated at the α position to give compounds having theformula III:

    Ar--N(--CH.sub.2-x Z.sub.x --R.sub.1 ')(--CH.sub.2-y Z.sub.y --R.sub.2 ')(III)

Z represents a halogen atom;

R₁ ' and R₂ ', which may be the same or different, are each a hydrogenatom or an alkyl radical having at most 4 carbons;

x and y, which may be the same or different, are each an integer of 0 or1, with the proviso that x+y is at least equal to 1; and

Ar is a deactivated aromatic ring, preferably derived from formula (I)by replacement of R₁ with a dialkylamine;

it being possible for R₁ ' and R₂ ' to be linked to make just a singleradical forming a ring with the nitrogen. Preferably, R₁ ' and R₂ ' areeach a hydrogen atom.

If the amount of halogenating agent is limited to the stoichiometricamount, or to an approximately 10% excess relative to the stoichiometryfor a single dealkylation, only one alkyl group is halogenated. If theamount of the halogenating agent is not limited, both alkyl groups willbe halogenated at the benzyl position. The choice of the stoichiometrytherefore makes it possible to choose between a halogenation of thering, a monodealkylation or a didealkylation.

The inventive dealkylation is especially surprising with respect to itsselectivity, since the meta positions are not affected and the carbonsof the alkyl chains situated at the α position with respect to theaniline function are not substantially affected more than once, therebymaking it possible to economize on expensive reactants and reducing theamounts of effluents. It is even possible to effect a selectivemonodealkylation of the aniline (in the broad sense of the term).

During the study which led to the present invention, it was shown thatthis halogenation involves only the alkyl carbons linked directly to theaniline function, and, if they are hydrogen atoms, the ortho and parasubstituents, or equivalent substituents, on the aromatic ring(s).

In general, this free radical halogenation step preferably takes placeat a temperature of between 0° and 100° C., and more preferably in theregion of a point between 0° C. and 50° C.

Preferably, the halogenation occurs in chlorinated or simply polarsolvents. When solvents are used whose boiling point is below 100° C.,it is practical to work at the reflux temperature. Thus, whereappropriate, it is practical to work under reduced pressure to bring therefluxing temperature to within the preferred range.

The free radical halogenation can introduce various halogens such asfrom chlorine, bromine or iodine into the molecule. In general, oneconomic grounds, chlorine is preferred. However, when it is desired tosupply a specific halogen to the ring, it is appropriate to use ahalogenating agent that supplies this halogen.

The same considerations apply when it is desired to avoid aperhalogenation of free ortho and para positions, or equivalentpositions, with respect to the aniline; in this case, halogenation isperformed with an agent that introduces a halogen of higher rank thanthose present in the ring, and dehydrohalogenation is then carried outby means that are known to those skilled in the art to be selective.

Any solvents which are inert under the reaction conditions may be usedfor the free radical halogenation. Such solvents include carbontetrachloride, chlorobenzene, dichlorobenzene and acetonitrile.

When the reactants are not naturally free-radical reactants, e.g.,thionyl or sulfuryl chlorides, they are preferably employed in thepresence of an agent or conditions promoting free-radical formation.Preferably, the agent is actinic radiation, which is known to thoseskilled in the art to promote the formation of Hal.sup.•.

Procedures for the hydrolysis of the compounds of formula III isgenerally known to those skilled in the art, and are preferably carriedout in the presence of an absorber of the acids released.

Unexpectedly, the intermediate products of formula

    Ar--N(--CH.sub.2-x Z.sub.x --R.sub.1 ')(CH.sub.2-y Z.sub.y --R.sub.2 ')(III)

are sufficiently stable to be able to be isolated, and constituteprecursors of a large number of chemical derivatives. These compoundsrepresent a fourth embodiment of the present invention. Preferably, Z isa chlorine atom, x=1 and y=1.

In addition, the isolation of these compounds from the reaction mediumenables a better purity of the totally or partially dealkylated anilineto be obtained; the separation is greatly facilitated by the fact thatthe compounds in which y=1 and x=1 are greatly preponderant in thereaction mixture.

As noted above, the halogenation-hydrolysis process for dealkylation ofalkylanilines may result in halogenation of the ortho positions of theparent alkylaniline. Accordingly, as an alternative, a third embodimentof the present invention is directed to a process for dealkylation ofdeactivated alkylanilines without affecting the initial aromaticradical, which comprises reacting the aniline with ammonia or a primaryor secondary amine, in free form or the form of one of its salts, in thepresence of a catalytic amount of a pyridine salt.

This surprising reaction possesses the advantage, for dialkylanilines,of being selective and of being possible even when the alkylanilines aresecondary.

As used herein, the term "amine" should be understood to include amixture of the amines defined above. The amine can also be a pyridine orsubstituted pyridine. As salts, amine hydrohalides, particularly aminehydrochlorides, are preferred.

As used herein, "pyridine" is intended to mean any compound possessing apyridine ring in which the nitrogen atom does not possess a substituent.Thus, pyridine should be understood to include not only pyridine itself,but also the chemical compounds originating from the substitution ofpyridine, including pyridines associated with other ring-system(s), forexample, quinoline. It is preferable for the substitutes for pyridineitself to possess a boiling point equal to not more than approximately200° C. Naturally, "pyridine" should also be understood to include amixture of the pyridines defined above. Preferably, the pyridineemployed is a pyridine hydrohalide salt, most preferably, pyridinehydrochloride, either alone or in the presence of the aminehydrochloride.

As with the halogenation-hydrolysis process, it is also possible withthis method to carry out a mono- or a didealkylation. In particular,there is monodealkylation when the acid corresponding to the pyridinesalt and/or to the amine salt is a relatively weak acid, i.e., one whosepKa is no less than 1, preferably no less than 3.

Preferably, the amine possess a pKa which is greater than that of thepyridine, preferably by at least two units and more preferably by twoand a half units.

Preferably, the process of dealkylation according to this thirdembodiment of the invention is carried out at a temperature of from 150°to 250° C.; more preferably from 180° to 220° C. It is preferred that anexcess of between 1 and 50 equivalents of amine be employed, morepreferably between 2 and 10 equivalents, relative to the stoichiometryof the demethylation. In a preferred embodiment, an excess of amine isemployed along with an excess of pyridine, preferably pyridinehydrochloride.

One of the most surprising and most advantageous aspects of thistechnique is that no lysis by ammonia or amine is observed, even in thecase where the aniline possesses a perfluoroalkyl group.

The dealkylation reaction is facilitated by the pKa of the acidassociated with the aniline being no greater than 5. Preferably, the pKaof the corresponding acid is no greater than 2, more preferably nogreater than 1, and most preferably no greater than 0.

The following examples are merely illustrative of the invention andshould not be construed as limiting. One skilled in the art can make,without undue experimentation, various substitutions and variations andby equivalent means, performing in substantially the same manner, obtainsubstantially the same results without departing from the teaching andspirit of the invention.

TYPICAL EXAMPLES ##STR5##

p-Chlorotrifluoromethylbenzene (1.29 g, 7.15 mmol) of DMF (4 g) andsodium amide (0.56 g, 14.3 mol) were introduced in order into a (100 ml)jacketed Teflon autoclave.

The autoclave was closed and the mixture was heated with stirring to180° C. for 24 h. After treatment of the reaction medium,para-trifluoromethyl-N,N-dimethylaniline was obtained (DC 74%, TY 77%).

    ______________________________________                                        *Influence of the solvent:                                                     ##STR6##                                                                     X = Br or preferably Cl                                                       Conditions: CF.sub.3 -Φ-Cl 0.322 g (1.79 mmol)                            NaNH.sub.2 0.14 g (53.6 mmol)                                                 DMF 4 g                                                                       (100 ml) jacketed Teflon autoclave.                                           Solvent      0° (C.)                                                                        t (H)   AY    DC    CY                                   ______________________________________                                        Example No. 1                                                                              210     24      57    82    70                                   DMF                                                                           Example No. 2                                                                              220     24      30    76    37                                   Dimethylacetamide                                                             Example No. 3                                                                              200     24      32    65    50                                   Tetramethylurea                                                               Example No. 4                                                                              210     24      30    96    32                                   Tetramethylguanidine                                                          ° Temperature range: 150-230° C. with DMF.                       ##STR7##                                                                     ______________________________________                                    

A 1-liter Hastelloy™ autoclave was charged with3,4-dichlorotrifluoromethylbenzene (47.1 g, 0.212 mol), DMF (200 g) andsodium hydroxide pellets (25.8 g, 0.645 mol).

The autoclave was closed and the mixture was heated with stirring to210° C. for 3 hours. The pressure reached 9 bars.

After treatment of the reaction medium,4-trifluoromethyl-2-chloro-N,N-dimethylaniline was obtained (DC 92%)(CY93%).

    __________________________________________________________________________            Example                                                                             Example                                                                             Example                                                                             Example                                                                             Example                                       *Parameter                                                                            No. 5 No. 6 No. 7 No. 8 No. 9                                         __________________________________________________________________________    3,4-Dichloro-                                                                         0.215 0.225 0.225 0.222 0.224                                         trifluoromethyl-                                                              benzene                                                                       (mmol)  1     1     1     1     1                                             DMF (g) 4     4     4     4     4                                             (equiv.)                                                                              55    55    55    55    55                                            NaOH (g)                                                                              --    --    0.044 0.048 --                                            (equiv.)                                                                              --    --    1.1   1.2   --                                            H.sub.2 O (g)                                                                         0.210 0.211 --    --    --                                            (equiv.)                                                                              12    12    --    --    --                                            NaOH 37% (g)                                                                          --    --    --    --    0.202                                         (equiv) --    --    --    --    1.8 NaOH                                                                      7 H.sub.2 O                                   θ (= ° C.)                                                               195   195   195   195   195                                           T (hours)                                                                             20    20    20    20    20                                            DC (%)  45    75    59    78    91                                            CY (%)  87    86    71    67    64                                            __________________________________________________________________________

EXAMPLE NO. 10

Sulfuryl chloride (9.5 g, 70 mmol) was added to a solution of2-chloro-4-trifluoromethyl-N,N-dimethylaniline (14.25 g, 63.8 mmol) incarbon tetrachloride (90 ml).

The experiment was carried out in the presence of a strong lamp and inthe absence of light. After heating to 70° C. for 2 hours, the solutionwas treated with an excess of 50% sodium hydroxide in water.

HPLC analysis of the organic phase showed the following results:

    ______________________________________                                                    2,6-dichloro-  2,6-dichloro-                                                  4-trifluoromethyl-                                                                           4-trifluoromethyl-                                 Conditions  N-N-dimethylaniline                                                                          N-methylaniline                                    ______________________________________                                        In presence of lamp                                                                       5-10%          85%                                                In daylight 68%            17%                                                In darkness 90%             0%                                                ______________________________________                                    

EXAMPLE NO. 11

A mixture of 2,6-dichloro-4-trifluoromethyl-N,N-dimethylaniline (4.5 g,17.4 mmol) and 2,6-dichloro-4-trifluoromethyl-Nmethylaniline (1.88 g,6.9 mmol) dissolved in carbon tetrachloride (60 ml) was treated withsulfuryl chloride (5.7 g, 42.2 mmol).

The reaction mixture, cooled to 10° C. was illuminated by means of a UVlamp for 6 hours, and then treated with an excess of 50% sodiumhydroxide in water. HPLC analysis of the organic phase showed thepresence of 2,6-dichloro-4-trifluoromethylaniline (70 mol%).

EXAMPLE NO. 12

2,6-Dichloro-4-trifluoromethyl-N-methylaniline (1.318 g, 5.4 mmol)dissolved in carbon tetrachloride (40 ml) was treated with sulfurylchloride (4.5 g, 33 mmol). The reaction mixture, cooled to 10° C., wasilluminated by means of a lamp for one hour, and then treated with anexcess of 50% sodium hydroxide in water. HPLC analysis of the organicshowed the presence of 2,6-dichloro-4-trifluoromethylaniline (83 mol%).

EXAMPLE 13

A theoretical amount of gaseous chlorine was introduced into a solutionof 2,6-dichloro-4-trifluoromethyl-N,N-dimethylaniline (3 g, 11.6 mmol)in carbon tetrachloride (60 ml).

During the introduction of chlorine, the reaction mixture was cooled to10° C. and illuminated by means of a UV lamp. HPLC analysis of theorganic phase after treatment showed, after 1 hour, a 92% conversion anda 64% yield of 2,6-dichloro-4-trifluoromethylaniline.

EXAMPLE NO. 14

A theoretical amount of gaseous chlorine was introduced into a solutionof 2,6-dichloro-4-trifluoromethyl-N,N-dimethylaniline (2.25 g, 8.7 mmol)in 1,2-dichlorobenzene (65 ml).

During the introduction of chlorine, the reaction mixture was cooled to10° C. and illuminated by means of a UV lamp.

HPLC analysis of the organic phase after treatment showed, at the end of50 minutes, a 99% conversion and a 92% yield of2,6-dichloro-4-trifluoromethylaniline.

EXAMPLE NO. 15

A theoretical amount of gaseous chlorine was introduced into a solution,cooled to 10° C., of 2,6-dichloro-4-trifluoromethylaniline (8.45 mmol)in 1.2 dichlorobenzene (65 ml). After illumination of the reaction massby means of a UV lamp for 15 minutes, the reaction was continued andprotected from light for 2 hours. HPLC analysis of the organic phaseafter treatment showed a 98% conversion and a 34% yield of2,6-dichloro-4-trifluoromethylaniline.

EXAMPLE NO. 16

1,2,3,-Trichlorobenzene (0.963 g), DMF (4 g) and sodium hydroxide (0.4g) were introduced in order into a (100 ml) jacketed Teflon autoclave.

The autoclave was closed and the mixture was heated with stirring to220° C. for 24 hours. The conversion was then 78%.

After treatment of the reaction medium, 0.517 g of the mixture ofN,N-dichlorodimethylanilines was brought into contact with pyridinehydrochloride (5.70 g).

The mixture was heated to 185° C. for 45 minutes.

HPLC analysis of the mixture showed the presence of 2,3-dichloroaniline(95%) and of 2,6-dichloroaniline (5%).

EXAMPLE NO. 17

1,2,4-Trichlorobenzene (0.766 g), DMF (4 g) and sodium hydroxide (0.4 g)were introduced in order into a (100 ml) jacketed Teflon autoclave.

The autoclave was closed and the mixture was heated with stirring to220° C. for 24 hours. The conversion was then 82%.

After treatment of the reaction medium, 0.223 g of the mixture ofchloro-N,N-dimethylanilines was brought into contact with pyridinehydrochloride (3.2 g).

The mixture was heated to 185° C. for 60 minutes.

HPLC analysis of the mixture showed the presence of 2,4-dichloroaniline(96%) and of 3,4-dichloroaniline (4%).

EXAMPLE NO. 18

1,2,4,5-Tetrachlorobenzene (0.919 g), DMF (4 g) and sodium hydroxide(0.4 g) were introduced in order into a (100 ml) jacketed Teflonautoclave.

The autoclave was closed and the mixture was heated with stirring to220° C. for 24 hours. The conversion was then 100%.

After treatment of the reaction medium, 0.50 g of the mixture oftrichloro-N,N-dimethylanilines was brought into contact with pyridinehydrochloride (5.8 g).

The mixture was heated to 190° C. for 60 minutes.

HPLC analysis showed the presence of 2,4,5-trichloroaniline (100%).

EXAMPLE NO. 19

2,6-Dichlorobromobenzene (0.992 g), DMF (4. g) and sodium hydroxide (0.4g) were introduced in order into a (100 ml) jacketed Teflon autoclave.

The autoclave was closed and the mixture was heated with stirring to220° C. for 24 hours. The conversion was then 89%.

After treatment of the reaction medium, 0.43 g of the mixture ofchloro-N,N-dimethylanilines was brought into contact with pyridinehydrochloride (5.2 g).

The mixture was heated to 190° C. for 60 minutes.

HPLC analysis of the mixture showed the presence of 2,6-dichloroaniline(43%) and of 2-bromo-3-chloro-aniline (57%).

EXAMPLE NO. 20

Pyridine hydrochloride (4.35 g, 37.7 mmol) was added to2,6-dichloro-4-trifluoromethyl-N,N-dimethylaniline (0.86 g, 3.3 mmol).

The mixture was heated to 185° C. for 2 hours.

HPLC analysis then showed the presence of2,6-dichloro-4trifluoromethylaniline (76 mol%).

EXAMPLE NO. 21 (Monodemethylation)

2,6-Dichloro-4-trifluoromethyl-N,N-dimethylaniline (0.86 g, 3.3 mmol)and pyridinium acetate (5 g) were introduced into a (100 ml) jacketedTeflon autoclave.

The autoclave was closed and the mixture was heated to 190° C. for 2hours.

HPLC analysis showed the presence of2,6-dichloro-4-trifluoromethyl-N-methylaniline (yld. 9 mol%).

EXAMPLE NO. 22 (comparative)

A mixture of 2,6-dichloro-4-trifluoromethyl-N,N-dimethylaniline (0.810g) and dimethylamine hydrochloride (3.5 g) was heated for 1 hour to 180°C.

HPLC analysis of the mixture indicated the absence of conversion.

EXAMPLE NO. 23

A mixture of 2,6-dichloro-4-trifluoromethyl-N,N-dimethylaniline (0.745g), pyridine hydrochloride (34 mg) and dimethylamine hydrochloride (3.24g) was heated for 1 hour to 180° C.

HPLC analysis of the mixture showed a yield (20%) of2,6-dichloro-4-trifluoromethylaniline which was three times as high astheory if the pyridine alone were active.

EXAMPLE NO. 24 (conventional technique)

A solution of 2,6-dichloro-4-trifluoromethyl-N,N-dimethylaniline (1 g)in aqueous hydrobromic acid (47%, 5 g) was brought to reflux for 5hours.

HPLC analysis of the mixture showed an 89% conversion and a 55% yield of2,6-dichloro-4-trifluoromethylaniline.

EXAMPLE NO. 25 (comparative)

The object was to demonstrate the failure of non-free-radicalhalogenation.

2-Chloro-6-nitro-N,N-dimethylaniline (0.802 g, 4 mmol) dissolved inchloroform (10 ml) was introduced into a 100-ml Teflon reactor. Asolution of bromine (0.64 g, 4 mmol) in chloroform (20 ml) was added tothis solution. The mixture was stirred at room temperature for 4 hours.Analysis of the reaction mixture showed that nothing other than thestarting material was present. (Analytical technique: gas chromatographyand mass spectroscopy)

EXAMPLE NO. 26 (comparative with U.S. Pat. No. 2,887,514)

It was sought to demonstrate the need for the presence of a base.

3,4-Dichloro-4-trifluoromethylbenzene (4.62 g, 21.4 mmol) anddimethylformamide (22 g, 14 molar equivalents) were introduced in orderinto a (100 ml) jacketed Teflon autoclave.

The autoclave was closed and the mixture was heated with stirring for 5hours to 200° C.

Analysis of the reaction medium by gas chromatography indicated a 3%conversion for a 2% yield of dimethylanilines.

3,4-Dichloro-4-trifluoromethylbenzene (4.62 g, 21.4 mmol),dimethylformamide (22 g, 14 molar equivalents) and solid sodiumhydroxide (0.856 g, 2.5 molar equivalents) were introduced in order intoa (100 ml) jacketed Teflon autoclave.

The autoclave was closed and the mixture was heated with stirring for 5hours of 200° C.

Analysis of the reaction medium by gas chromatography indicated a 95%conversion for an 80% yield of 2-chloro-4-trifluoromethylaniline.

EXAMPLE NO. 27 (Examples of regeneration of pyridinium compounds andrecycling process)

Pyridine hydrochloride may be readily obtained by techniques which areknown to a person skilled in the art, for example, treatment of pyridinewith a stoichiometric amount of a 36% solution of hydrochloric acid inwater followed by azeotropic distillation of the water with toluene.

Process

2,6-Dichloro-4-trifluoromethyldimethylaniline (1.72 g, 6.6 mmol) washeated to 180° C. for 1 hour in the presence of pyridine hydrochloride(8.7 g, 37.7 mmol). An assay of the reaction mass indicated a 100%conversion. The reaction medium was then cooled to 140° C., andorthoxylene (5 ml) was added with stirring. At the end of 2 minutes,stirring was stopped and a separation into two layers occurred. Theupper phase was recovered. Analysis by gas chromatography showed thepresence of 2,6 dichloro-4-trifluoromethylaniline (1.47 g, 97% yield).

The lower phase containing a mixture of methylpyridinium and pyridiniumhydrochlorides was regenerated at 200° C. by the action of ammonia. Thepyridine recovered by distillation may be recycled.

Although preferred embodiments of the invention are described herein indetail, it will be understood by those skilled in the art thatvariations may be made thereto without departing from the spirit of theinvention or the scope of the appended claims.

I claim:
 1. A process for dealkylating a deactivated aniline, which comprises reacting said aniline with ammonia or a primary or secondary amine in the presence of a catalytic amount of a pyridine salt.
 2. The process according to claim 1, wherein said pyridine salt is a pyridine hydrohalide.
 3. The process according to claim 2, wherein said pyridine salt is pyridine hydrochloride.
 4. The process according to claim 1, wherein said amine has a pKa which is greater than that of said pyridine salt.
 5. The process according to claim 4, wherein said amine has a pKa which is at least 2 units greater than that of said pyridine salt.
 6. The process according to claim 1, wherein said reaction is performed at a temperature of between 150° C. and 250° C.
 7. The process according to claim 6, wherein said reaction is performed at a temperature of between 180° C. and 220° C.
 8. The process according to claim 1, wherein said amine is a mixture of amines.
 9. The process according to claim 1, wherein said amine is pyridine or substituted pyridine.
 10. The process according to claim 1, wherein said amine is an amine hydrohalide.
 11. The process according to claim 1, wherein said amine is an amine hydrochloride.
 12. The process according to claim 1, wherein said pyridine salt is a quinoline salt.
 13. The process according to claim 1, wherein said pyridine salt is a mixture of pyridine salts.
 14. The process according to claim 1, wherein an excess of between 1 and 50 equivalents of amine is used, relative to the stoibichiometry of dealkylation.
 15. The process according to claim 1, wherein an excess of between 2 and 10 equivalents of amine is used, relative to fine stoichiometry of dealkylation.
 16. The process according to claim 1, wherein an excess of amine and an excess of pyridine salt are used.
 17. The process according to claim 1, wherein acid associated with the aniline has a pKa no greater than
 5. 18. The process according to claim 1, wherein acid associated with the aniline has a pKa no greater than
 1. 19. The process according to claim 1, wherein acid associated with the aniline has a pKa no greater than zero. 